More than 12,000 new cases of thyroid cancer develop each year in the United States, and because patients usually survive for many years, the prevalence is much higher. Currently, the mortality rate of thyroid cancer is the highest among cancers affecting the endocrine glands (excluding the ovary). This is in part due to conservative treatment of thyroid cancer because clinicians perceive the 9% mortality rate as relatively nonthreatening. However, the long-standing differential tumors occasionally alter abruptly their growth characteristics, grow rapidly, and do not respond to current treatments. Unfortunately, a tumor's behavior often cannot be anticipated clearly from its initial clinical features, making it difficult to consistently identify patients who will experience a poor outcome. Therefore, the long-term goal of this research is to investigate the molecular mechanisms underlying the wide spectrum of clinical behavior in thyroid cancer, and ultimately, to improve treatment of patients with thyroid cancers. Recently, the PTC oncogene, an activated form of the ret proto-oncogene, has been found specifically and consistently in 11-25% of human papillary thyroid carcinomas (PC). Moreover, PTC has demonstrated transforming activity in NIH/3T3 cells, and our previous study indicated that PTC in PC may be a useful marker in patients destined to develop distant metastases. These findings lead to the hypothesis that PTC may have a direct involvement in the pathogenesis of PC and PTC expression in PC may portend a poor prognosis. The specific aims of the proposed research are: (i) To correlate PTC expression with tumor progression in human thyroid cancers. (ii) To investigate molecular mechanism of the PTC transforming activity. (iii) To investigate mechanisms underlying the thyroid-specificity of PTC. The proposed research will explore the potential of using PTC as a molecular marker for diagnosis, and/or poor prognosis in patients with differentiated papillary thyroid carcinoma. Furthermore, while investigating the mechanism underlying the thyroid- specificity of PTC, the information obtained may also provide a unique avenue for studying the etiology of PC. Finally, investigating the mechanism of PTC transforming activity will serve as a basis for further research on how this fused protein is involved in the development of PC. In so doing, we will be able to understand the molecular mechanisms and biochemical changes involved in thyroid neoplastic transformation, and ultimately, the actual mechanisms underlying the wide spectrum of thyroid cancers.